Protein kinase C (PKC) is a family of calcium stimulatable and phospholipid-dependent serine/threonine-specific protein kinases which play an important role in cellular growth control, regulation, and differentiation. protein kinase C is also fundamental to the processes involved in tumorigenicity, since it is the major high-affinity receptor for several classes tumor promoters as well as for endogenous cellular diacylglycerols. These tumor promoters also stimulate protein kinase C catalysis. Castagna et al. (1982) J. Biol. Chem. 257: 7847 reported direct activation of protein kinase C by tumor-promoting phorbol esters. The mechanisms of protein kinase C action have been described in U.S. Pat. No. 4,816,450 issued Mar. 28, 1989 to Bell et al., the disclosures of which are specifically incorporated as if fully set forth herein. protein kinase C is activated by diacylglycerol (DAG), a neutral lipid, and when activated will transfer the .gamma.-phosphate of MgATP to a serine or threonine residue on a substrate protein.
Since the activation of protein kinase C have been implicated in several human disease processes, including cancer tumors, inflammation, and reperfusion injury, inhibition of protein kinase C should be of great therapeutic value in treating these conditions.
Protein kinase C inhibitors have been reported to potentiate the antitumor activity of cis-platin both in vitro and in vivo (Grunicke et al. (1989) Adv. Enzyme Regul. 28: 201; and German Offenlegungsschrift DE 3827974). In addition, it has been suggested that protein kinase C would be a potential target for therapeutic design because of its central role in cell growth (Tritton, T. R. and Hickman, J. A. Cancer Cells 2: 95-102 (1990)).
Protein kinase C inhibitors have been demonstrated to block platelet aggregation and release of neutrophil activating agents such as platelet activating factor (PAF) (Schachtele et al. (1988) Biochem. Biophy. Res. Commun. 151: 542; Hannun et al. (1987) J. Biol. Chem. 262: 13620; Yamada et al. (1988) Biochem. Pharmacol. 37: 1161). protein kinase C inhibitors have also been shown to inhibit neutrophil activation, and chemotactic migration (McIntyre et al. (1987) J. Biol Chem. 262: 15730; Lambreth et al. (1988) J. Biol. Chem. 263: 3818; Pittet et al. (1987) J. Biol. Chem. 262: 10072; and Gaudry et al. (1988) Immunology 63: 715), as well as neutrophil degranulation and release of proteolytic enzymes and reactive oxygen intermediates (Wilson et al. (1986) J. Biol. Chem. 261: 12616; Fujita et al. (1986) Biochem. Pharmacol. 35: 4555; Berkow et al. (1987) J. Leukoc., Biol. 41: 441; Salzer et al. (1987) Biochem. Biophys. Res. Commun. 148: 747; Kramer et al. (1989) J. Biol. Chem. 262: 5876; and Dewald et al. (1989) Biochem. J. 264: 879). Thus inhibitors of protein kinase C have the capability of blocking all three of the most significant mechanisms of pathogenesis associated with myocardial reperfusion injury, and should thus have a decided therapeutic advantage. Additionally, the inhibitory effect of protein kinase C inhibitors on keratinocytes, and on the oxidative burst in neutrophils will lead to an anti-inflammatory effect.
Substituted anthraquinones have been reported for various uses, including cancer treatment. U.S. Pat. No. 3,960,751 issued Jun. 1, 1976 to Moriyama et al. discloses substituted anthraquinones useful as pleochroic dyes. U.S. Pat. No. 4,598,155 issued Jul. 1, 1986 to Adam discloses tetrazole substituted anthraquinones useful as dyes.
U.S. Pat. No. 4,762,648 issued Aug. 9, 1988 to Stache et al. discloses mono-functional and bis-functional anthraquinone-(oxy-2,3-oxidopropanes) useful as intermediates in the preparation of drugs possessing .beta.-receptor blocker action and as crosslinking agents in the preparation of polymers. The compounds also exhibit cytostatic activity.
Several patents disclose the use of substituted anthraquinones for treatment of neoplasms. U.S. Pat. No. 4,894,451 issued Jan. 16, 1990 to Krapcho et al. discloses unsymmetrical 1,4-bis-(aminoalkylamino)-anthracene-9,10-diones useful in the treatment of neoplasms. U.S. Pat. No. 4,310,666 issued Jan. 12, 1982 to Zee-Cheng et al discloses 1,4-bis-(substituted aminoalkylamino)-anthraquinones useful in the treatment of neoplasms. U.S. Pat. No. 4,526,989 issued Jul. 2, 1985 to Murdock et al discloses symmetrical 1,4-bis(substituted-amino)-5,8-dihydroxyanthraquinones useful as chelating agents and for inhibiting the growth of tumors. U.S. Pat. No. 4,197,249 issued Apr. 8, 1980 to Murdock et al also discloses symmetrical 1,4-bis(substituted-amino)-5,8-dihydroxyanthraquinones useful as chelating agents and for inhibiting the growth of tumors. U.S. Pat. No. 4,540,788 issued Sep. 10, 1985 to Murdock discloses 1,4-bis[-aminoalkyl)amino]-9,10-anthracenediones and leuco bases thereof which are useful as chelating agents and for inducing regression of leukemia and/or inhibition of tumor growth in mammals. Japanese patent 19819 issued May 7, 1990 discloses substituted anthraquinones having substituents at positions 5 and 6 of the anthraquinone ring structure which are useful as anti-tumor agents alone or in combination with other anti-tumor agents.
German Offenlegungsschrift DE 3827974 A1 discloses therapeutic preparations comprising a protein kinase C inhibitor in combination with a lipid, a lipid analogue, a cytostatic agent or phospholipase inhibitor useful for cancer therapy. However, none of the protein kinase c inhibitors disclosed in this publication are substituted anthraquinones.
Although substituted anthraquinones have been reported for cancer treatments, substituted anthraquinones such as Mitoxantrone, are known to be associated with side effects mainly immunosuppressive activity, and drug resistance. Accordingly novel cancer treatments that avoid some or all of these drawbacks are needed.
Further, inflammation and reperfusion injury, particularly pertaining to cardiac injury, are common conditions for which there exists no definitive treatment despite extensive research and appropriate treatments for these conditions are needed.